@article{80cce8a93b2c4d549457e8c2df63e01f,
title = "CSF-1R inhibition alters macrophage polarization and blocks glioma progression",
abstract = "Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs). Macrophages depend on colony stimulating factor-1 (CSF-1) for differentiation and survival. We used an inhibitor of the CSF-1 receptor (CSF-1R) to target TAMs in a mouse proneural GBM model, which significantly increased survival and regressed established tumors. CSF-1R blockade additionally slowed intracranial growth of patient-derived glioma xenografts. Surprisingly, TAMs were not depleted in treated mice. Instead, glioma-secreted factors, including granulocyte-macrophage CSF (GM-CSF) and interferon-γ (IFN-γ), facilitated TAM survival in the context of CSF-1R inhibition. Expression of alternatively activated M2 markers decreased in surviving TAMs, which is consistent with impaired tumor-promoting functions. These gene signatures were associated with enhanced survival in patients with proneural GBM. Our results identify TAMs as a promising therapeutic target for proneural gliomas and establish the translational potential of CSF-1R inhibition for GBM.",
author = "Pyonteck, {Stephanie M.} and Leila Akkari and Schuhmacher, {Alberto J.} and Bowman, {Robert L.} and Lisa Sevenich and Quail, {Daniela F.} and Olson, {Oakley C.} and Quick, {Marsha L.} and Huse, {Jason T.} and Virginia Teijeiro and Manu Setty and Leslie, {Christina S.} and Yoko Oei and Alicia Pedraza and Jianan Zhang and Brennan, {Cameron W.} and Sutton, {James C.} and Holland, {Eric C.} and Dylan Daniel and Joyce, {Johanna A.}",
note = "Funding Information: We thank K. Simpson and X. Chen for excellent technical support, members of the Joyce and Holland labs, particularly T. Ozawa, K. Pitter and M. Squatrito, for technical advice and reagents and D. Chakravarti and the MSKCC Brain Tumor Center for assistance with patient and tumor sphere line information. We thank R. Benezra, K. Hunter and H.-W. Wang for reading the manuscript. We thank E. Pamer and T. Hohl (MSKCC) for providing CCR2-DTR mice and R. Lang (Cincinnati Children{\textquoteright}s Hospital Medical Center) for providing CD11b-DTR mice. We are grateful to the MSKCC Core Facilities of Genomics, Flow Cytometry and Small Animal Imaging, Geoffrey Beene Translational Oncology and the Novartis Institutes for BioMedical Research Emeryville Analytical Sciences group for technical assistance. This research was supported by US National Cancer Institute program grants of the Integrative Cancer Biology Program (CA148967; J.A.J. and C.S.L.) and Tumor Microenvironment Network (CA126518; J.A.J. and E.C.H.), Cycle for Survival (J.A.J.), the Geoffrey Beene Foundation (J.A.J., R.L.B. and O.C.O.), the MSKCC Brain Tumor Center (J.A.J. and L.A.), the Fundaci{\'o}n Ram{\'o}n Areces and Ibercaja (A.J.S.), Deutsche Forschungsgemeinschaft (L.S.), Canadian Institutes of Health Research (D.F.Q.), US National Institutes of Health T32 Institutional Research training grant (5T32GM008539, S.M.P.), US National Cancer Institute F31 fellowships (F31CA167863, R.L.B.; F31CA171384, O.C.O.) and Cornell and Gerstner Sloan Kettering graduate programs (S.M.P., R.L.B., O.C.O. and V.T.).",
year = "2013",
month = oct,
doi = "10.1038/nm.3337",
language = "English (US)",
volume = "19",
pages = "1264--1272",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "10",
}